Tesofensine and beta blocker combination formulations

ABSTRACT

The present invention relates to a controlled release formulation comprising the active compounds tesofensine and a beta blocker, such as metoprolol or carvedilol, or a pharmaceutically acceptable salt thereof. The invention further relates to use of the controlled release formulation in a method of treatment of diabetes, obesity, or an obesity associated disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/554,449, filed Aug. 30, 2017, which is a national stage entry ofInternational Application No. PCT/DK2016/050058, filed Mar. 2, 2016,which claims the benefit of Denmark Application Nos. PA 2015 70117,filed Mar. 3, 2015, and PA 2015 70644, filed Oct. 9, 2015, theentireties of which are incorporated herein in their entireties.

FIELD OF INVENTION

The present invention relates to a new controlled release formulationscomprising the active compounds tesofensine and a beta blocker, such asmetoprolol or carvedilol, or pharmaceutically acceptable salts thereof.

BACKGROUND OF INVENTION

Within the past decades the prevalence of obesity has risen in virtuallyall ethnic, racial and socioeconomic populations, in both genders and inall age groups. Obesity is associated with a significantly elevated riskfor type 2 diabetes, coronary heart diseases, hypertension and numerousother major illnesses and overall mortality from all causes. Therefore,weight reduction is critical for the obese patient. Thus there isimpetus for creating new and alternative treatments for management ofobesity.

Tesofensine, i.e.[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane],first described in WO 97/30997, is a triple monoamine reuptake inhibitorin development for the treatment of obesity.

Tesofensine effectively produces a weight loss in obese individuals ofabout twice of that seen with currently marketed anti-obesity drugs.Results from clinical studies with Tesofensine also showed that thecompound has a good safety profile and is well tolerated. However,though no clinically relevant cardiovascular adverse events or changesin either blood pressure or pulse were seen, some cardiovascular effectswere measured with slight increases in heart rate and trends in bloodpressure. Although such small effects have no immediate risk to thepatient, some medical and regulatory concerns have been raised based onobservational studies, that even small changes in cardiovascularparameters may have long term implications on patients' benefit/riskevaluation.

Preclinical and clinical data suggest that appetite suppression is animportant mechanism by which Tesofensine exerts its robust weightreducing effect. Notably, the strong hypophagic response (i.e. lessappetite, decreased feeding) to Tesofensine treatment is demonstrated tobe linked to central stimulation of noradrenergic and dopaminergicneurotransmission. However, the sympathomimetic mode of action ofTesofensine may also associate with the elevated heart rate and bloodpressure observed in clinical settings.

Beta blockers, (β-blockers, beta-adrenergic blocking agents, betaantagonists, beta-adrenergic antagonists, beta-adrenoreceptorantagonists, or beta adrenergic receptor antagonists) are a class ofdrugs that are typically used for the management of cardiac arrhythmias,protecting the heart from a second heart attack (myocardial infarction)after a first heart attack (secondary prevention), and, in certaincases, hypertension. Beta blockers are also well known for theirreductive effect on heart rate.

Metoprolol, i.e.1-(Isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol, brandedunder various trade names, is a selective β1 (adrenergic) receptorblocker normally used in the treatment of various disorders of thecardiovascular system, and in particular hypertension.

Carvedilol((±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine)is a mixed, i.e. nonselective alpha and beta blocker. It is marketedunder various trade names and is traditionally used in the treatment ofmild to severe congestive heart failure (CHF) and high blood pressure.

WO 2013/120935 describes treatment of obesity by co-administration oftesofensine and metoprolol in order to ameliorate drug-induced elevationof blood pressure or increase in heart rate.

The serum half-life of tesofensine is nine days (Bara-Jimenez W,Dimitrova T, Sherzai A, Favit A, Mouradian M M, Chase T N (2004).“Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson'sdisease”. Mov Disord 19 (10): 1183-6.). In comparison, the half-life ofbeta blockers is quite short with metoprolol in the order of 3-4 hoursand carvedilol about 7 to 10 hours. Therefore simultaneous dailyadministration of these two drugs is likely to induce high fluctuationsin the serum levels of the beta blocker and potentially recurrenttemporary absence of therapeutic efficacy of the beta blocker.

SUMMARY OF DISCLOSURE

The present disclosure relates to pharmaceutical compositions comprising

a. a first composition comprising an extended release composition of anactive pharmaceutical ingredient (API) selected from a beta blocker or apharmaceutically acceptable salt thereof,b. a second composition comprising active pharmaceutical ingredient(API) selected from tesofensine or a pharmaceutically acceptable saltthereof, andc. a third composition comprising an immediate release composition of anactive pharmaceutical ingredient (API) selected from a beta blocker or apharmaceutically acceptable salt thereof.

The pharmaceutical composition is effective in treating obesity withoutcausing the undesired increase in heart rate and blood pressure observedfor treatment with tesofensine alone. The release profiles of the threecomponents of the pharmaceutical compositions are chosen carefully toprevent the side effects while maintaining the therapeutic efficacy oftesofensine.

The beta blocker may for example be selected from metoprolol, carvedilolor pharmaceutically acceptable salts thereof.

The second composition may be a first coating applied to the firstcomposition.

The third composition may be a second coating applied to the firstcoating.

The first composition may be coated with a coating comprising the secondand third composition.

The first composition may constitute a tablet core coated with a coatingcomprising the second and third composition. Alternatively, the firstcomposition may comprise a tablet core coated with a first coatingcomprising the second composition, wherein the first layer is coatedwith a second coating comprising the second composition.

In some embodiments, the first composition comprises pellets comprising:

a. an inert pellet core;b. a drug layer comprising the active pharmaceutical ingredient, whichlayer covers the inert core; andc. a controlled release layer thereon.

The inert core may comprise sugar spheres coated with a plasticized filmsub-coat of a hydrophobic film coating polymer plasticized with ahydrophilic and a hydrophobic plasticizer; the drug layer comprises APIand a binder; the controlled release layer comprises a plasticized filmcoat of a hydrophobic film coating polymer plasticized with ahydrophilic and a hydrophobic plasticizer, and wherein the pellets aremixed with a final tableting blend e.g. comprising a powder mixture ofone or more of fillers, disintegrants, glidants and/or lubricants.

In one embodiment, the hydrophobic film coating polymer comprises ethylcellulose, the hydrophilic plasticizer comprises polyethylene glycol,the hydrophobic plasticizer comprises dibutyl sebacate, the API ismetoprolol succinat, the binder comprises povidone, and the powdermixture comprises STARLAC (an excipient that is 85% of alpha-lactosemonohydrate and 15% white maize starch) (MEGGLE Group, Germany), SYLOID(silica) (W.R. Grace & Co.), crospovidone and magnesium stearate.

In another embodiment, the extended release layer comprises an admixtureof the following components:

a. an ethylacrylate/methylmethacrylate copolymer,b. a surfactant, andc. sodium stearyl fumarate,wherein the controlled release layer has been deposited from awater-containing liquid and the amount of theethylacrylate/methylmethacrylate copolymer in the film coat is in therange of 80-99.5% (w/w).

The composition may be in the form of a pharmaceutical dosage form, suchas a tablet or a capsule. A tablet may comprise an outer cosmetic filmcoat.

In another aspect, the composition is for use in a method of treatment,prevention or alleviation of obesity or an obesity-related disorder.

In yet another aspect, the present invention relates to use of thecomposition as described herein in the manufacture of a medicament forthe treatment of obesity or an obesity-related disorder.

The obesity associated disorder may be a disorder or condition selectedfrom the group consisting of type 2 diabetes, pre-diabetes, type 1diabetes (diabetes mellitus), metabolic syndrome, dyslipidemia,atherosclerosis, drug-induced obesity, overeating disorders, bulimianervosa, binge eating disorder, compulsive over-eating, impairedappetite regulation, nonalcoholic fatty liver disease (NAFLD), andnonalcoholic steatohepatitis (NASH).

In one embodiment, the obesity-associated disorder or condition is type2 diabetes.

In one embodiment, the obesity-associated disorder or condition isnonalcoholic fatty liver disease (NAFLD) and/or nonalcoholicsteatohepatitis (NASH).

In another aspect, the composition is for use in a method of treatment,prevention or alleviation of diabetes, preferably type 2 diabetes.

In another aspect, the composition is for use in a method of treatment,prevention or alleviation of nonalcoholic fatty liver disease (NAFLD)and/or nonalcoholic steatohepatitis (NASH).

In another aspect, the composition is for use in a method of decreasingliver fat and/or visceral adiposity.

Preferably the composition is administered once daily.

DESCRIPTION OF DRAWINGS

FIG. 1A: Calculated dissolution profile for tablet with 25 mg IRmetoprolol and 100 mg ER metoprolol. Calculated dissolution profile ofmetoprolol over 24 hours using USP Type II apparatus, rotating paddle,with 900 ml of Phosphate buffer at pH 7.4, 37° C. set at rotating speedof 75 rpm.

FIG. 1B: Calculated dissolution profile for tablet with 10 mg IRmetoprolol and 100 mg ER metoprolol. Calculated dissolution profile ofmetoprolol over 24 hours using USP Type II apparatus, rotating paddle,with 900 ml of Phosphate buffer at pH 7.4, 37° C. set at rotating speedof 75 rpm.

FIG. 2A: Schematic cross-sections of tablet with beta blocker ER (A),beta blocker IR (B) and Tesofensine (C) phases. A three layered tabletwith a core of beta blocker ER and two coatings of beta blocker IR andTesofensine.

FIG. 2B: Schematic cross-sections of tablet with beta blocker ER (A),beta blocker IR (B) and Tesofensine (C) phases. As in 2A but with theorder of the coatings reversed.

FIG. 2C: Schematic cross-sections of tablet with beta blocker ER (A),beta blocker IR (B) and Tesofensine (C) phases. A two layered tabletwith a core of beta blocker ER and one coating of beta blocker IR andTesofensine.

FIG. 2D: Schematic cross-sections of tablet with beta blocker ER (A),beta blocker IR (B) and Tesofensine (C) phases. A one layered tabletwith beta blocker ER spheres/granules in a binding matrix comprisingbeta blocker IR and Tesofensine.

FIG. 3: Release of Metoprolol from Metoprolol 100 mg ER tablets withcombined Tesofensine/Metoprolol film applied (example 7) and Metoprolol100 mg ER tablets with separate Tesofensine—and Metoprolol IR filmsapplied (Example 6).

FIG. 4: The expected dissolution profile for Carvedilol in apharmaceutical product comprising 80 mg extended release Carvedilol and20 mg immediate release Carvedilol

DEFINITIONS

Extended release—ER—also known as sustained-release [SR],extended-release [ER, XR, XL], and controlled-release [CR], is amechanism used in pill tablets or capsules to dissolve a drug over timein order to be released slower and steadier into the bloodstream.

Immediate release—IR. The drug is released (dissolved) immediately afteringestion.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are pharmaceutical compositions comprising twodifferent phases of a beta blocker, and one phase of tesofensine. Onephase of the beta blocker is an extended release phase and the otherphase is an immediate release phase.

The beta blocker may for example be metoprolol or carvedilol orpharmaceutically acceptable salts thereof. These include the phosphate,succinate, maleate, sulfate, glutarate, lactate, benzoate, and mandelatesalts.

The in vitro bio-dissolution profile (as determined by USP Type IIapparatus, rotating paddle, with 500 ml of Phosphate buffer at pH 7.4,37° C. set at rotating speed of 50 rpm) of the beta blocker ispreferably as follows:

Dissolution time Range  1 hour 10-35%  4 hours 25-45%  8 hours 45-65% 20hours >80%

For example, the combined in vitro bio-dissolution profile of metoprololpreferably has a dissolution profile lying within one or more of thefollowing release ranges for different metoprolol IR:ER ratios atvarious time points (as determined by USP Type II apparatus, rotatingpaddle, with 900 ml of Phosphate buffer at pH 7.4, 37° C. set atrotating speed of 75 rpm).

Calculated Calculated dissolution dissolution Dis- Dis- 10 mgDissolution 25 mg solution solution IR + ranges IR + ranges Overall time100 mg ER (10:100) 100 mg ER (25:100) range  1 hour 13% 10-20% 23%20-30% 10-30%  4 hours 29% 20-40% 38% 30-50% 20-50%  8 hours 53% 40-65%58% 50-70% 40-70% 24 hours 88% >80% 90% >80% >80%  1 hour 13% 10-20% 23%20-30% 10-30%  4 hours 29% 20-40% 38% 25-50% 20-50%  8 hours 53% 40-65%58% 40-70% 40-70% 20 hours 88% >80% 90% >80% >80%

In general the tesofensine of the composition is dissolved within ½-1hour. The in vitro dissolution profile with tesofensine under theconditions above is at least 80% of the API within 45 minutes.

Many physiological factors influence both the gastrointestinal transittime and the release of a drug from a controlled release dosage form,and thus influence the uptake of the drug into the systemic circulation.A sustained-release dosage form should release the beta blocker at acontrolled rate such that the amount of active ingredient available inthe body to treat the condition is maintained at a relatively constantlevel over an extended period of time. The release of an activeingredient from a controlled release dosage form is generally controlledby diffusion through a coating.

It is likewise important that part of the beta blocker is releasedrapidly so that a therapeutically effective level of the beta blocker isreached rapidly.

Tesofensine

The pharmaceutical composition described herein comprises an activepharmaceutical ingredient (API) selected from tesofensine or apharmaceutically acceptable salt thereof.

Tesofensine[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane]is a centrally acting triple monoamine re-uptake inhibitor (MRI) withintrinsic inhibitory activity on noradrenaline, serotonin and dopaminetransporter function. When corrected for placebo and diet effects,long-term Tesofensine treatment produces a weight loss of about 10% inobese patients, which is twice as much as that achieved by currentlymarketed anti-obesity drugs.

The chemical structure of Tesofensine is

Preclinical and clinical data suggest that appetite suppression is animportant mechanism by which Tesofensine exerts its robustweight-reducing effect. In addition, Tesofensine has also beendemonstrated to increase nocturnal energy expenditure in human subjects.These findings have recently been corroborated and extended inpreclinical settings, demonstrating that Tesofensine induces a robustand sustained weight loss in a rat model of diet-induced obesity (DIO)of which the long-lasting reduction in body weight is caused by appetitesuppression with a gradual increase in energy expenditure. Notably, thehypophagic effect of Tesofensine in DIO rats is critically dependent onstimulated al adrenoceptor activity, and to a less extend dopamine D1receptor function, indicating that enhancement of central noradrenergicand dopaminergic neurotransmission constitute important mechanismsunderlying the robust appetite-suppressing effect of Tesofensine.

Overall, chronic Tesofensine treatment is associated with minor adverseevents, and with minimal cardiovascular effects, suggesting thatTesofensine may generally be a well-tolerated long-term treatment forobesity. However, dose-dependent elevations in heart rate andsignificant increases in blood pressure have been reported in obeseindividuals. The long-term implications of such Tesofensine-inducedcardiovascular effects are not known and can potentially play a role inthe benefit/risk evaluation of patients treated with Tesofensine.

Beta Blockers

The present invention involves the use of beta blockers. The betablocker may be any conventional beta blocker known in the art.Preferably, the beta blocking drug is selected from the following groupsof compounds, which groups of compounds are known in the art and may becommercially available under different brand names, or may be obtainedas described in the literature.

Non-Selective Beta Blockers

In one embodiment, the beta blocker is a non-selective beta blocker.Examples of non-selective beta blockers include alprenolol, amosulalol,bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol,oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.

In one embodiment, the beta blocker is selected from the groupconsisting of alprenolol, amosulalol, bucindolol, carteolol,levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol,pindolol, propranolol, sotalol, timolol and pharmaceutically acceptablesalts thereof.

Beta 1-Selective Beta Blockers

In another embodiment, the beta blocker is a beta 1-selective betablocker.

Examples of beta 1-selective beta blockers include acebutolol, atenolol,betaxolol, bisoprolol, esmolol, landiolol, metoprolol and nebivolol.

In one embodiment, the beta blocker is selected from the groupconsisting of acebutolol, atenolol, betaxolol, bisoprolol, esmolol,landiolol, metoprolol, nebivolol and pharmaceutically acceptable saltsthereof.

In a particular embodiment, the beta blocker is metoprolol or apharmaceutically acceptable salt thereof.

Mixed Alpha and Beta Blockers

In a still further embodiment, the beta blocker is a mixed alpha andbeta blocker.

Examples of mixed alpha and beta blockers include carvedilol, celiprololand labetalol.

In one embodiment, the beta blocker is selected from the groupconsisting of carvedilol, celiprolol, labetalol and pharmaceuticallyacceptable salts thereof.

In a particular embodiment, the beta blocker is carvedilol or apharmaceutically acceptable salt thereof.

Beta 2-Selective Beta Blockers

In a still further embodiment, the beta blocker is a beta 2-selectivebeta blocker.

One example of a beta 2-selective beta blocker is butaxamine.

In one embodiment, the beta blocker is butaxamine or a pharmaceuticallyacceptable salt thereof.

Pharmaceutically Acceptable Salts

Examples of pharmaceutically acceptable salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzene-sulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Examples of pharmaceutically acceptable cationic salts of an APIinclude, without limitation, the sodium, the potassium, the calcium, themagnesium, the zinc, the aluminium, the lithium, the choline, thelysinium, and the ammonium salt, and the like, of an API containing ananionic group. Such cationic salts may be formed by procedures wellknown and described in the art.

In the context of this disclosure the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

In one embodiment of the present disclosure, Tesofensine is selectedfrom the free base, the citrate salt and the tartrate salt.

Suitable pharmaceutically acceptable salts of metoprolol include any ofthe salts mentioned herein and preferably include the tartrate,succinate, fumarate or benzoate salts and especially the succinate salt.The S-enantiomer of metoprolol or a salt thereof, particularly thebenzoate salt or the sorbate salt, may also be used.

Similarity Factors

Similarity factor (f2) is a recognized method for the determination ofthe similarity between the dissolution profiles of a reference and atest compound. Similarity factor (f2) is a logarithmic transformation ofthe sum of squared error. The similarity factor (f2) is 100 when thetest and reference profiles are identical and approaches zero as thedissimilarity increases. The similarity factor has also been adapted toapply to the determination of the similarity between the dissolutionprofiles of a reference and test compound as they relate to modifiedrelease formulations, such as those exemplified herein.

The f2 similarity factor has been adopted in the SUP AC guidelines andby the FDA guidance on dissolution testing of immediate release dosageforms (FDA Guidance for Industry, Dissolution Testing of ImmediateRelease Solid Oral Dosage Forms, FDA, (CDER), August 1997 (DissolutionTech. 4, 15-22, 1997)).

Preferably the pharmaceutical composition has a beta blocker in vitrodissolution profile generated using the USP Type II apparatus, rotatingpaddle method as described herein with a similarity factor (f2) between50 and 100 when calculated using one of the examples from FIG. 1 or FIG.3 as the reference profile.

API Amounts and Ratios

The ratio of extended release beta blocker, such as metoprolol, toimmediate release beta blocker may be 75-95:25-5. Suitably, the betablocker, such as metoprolol, in a dosage form is approximately an 80:20ratio of extended release to immediate release amounts. In anotherembodiment, the beta blocker, such as metoprolol, is in an approximate90:10 or 100:10 ratio of extended to immediate release amounts. In stillanother embodiment the ratio is approximately 80:20 or 75:25. Explaineddifferently, for unit dosage form, such as a tablet, containing 125 mgbeta blocker, such as metoprolol, the beta blocker may be present in anamount of about 100 mg in the extended release phase and about 25 mg inthe immediate release phase. For a unit dosage form comprising 110 mgbeta blocker, such as metoprolol, the beta blocker ER may be present inan amount of 100 mg and the beta blocker IR may be present in an amountof 10 mg. For example, in one embodiment, the ratios of extended releaseto immediate release phase represent the proportional amount of eachlayer in a bi-layer dosage form. In another embodiment, the ratiosrepresent the amount of metoprolol in the extended release intragranularcomponent versus the immediate release extragranular component of asingle layer dosage form. The rations and amounts mentioned in thecurrent paragraph apply well to metoprolol as the beta-blocker.

Preferably one dosage form comprises an amount of beta blocker, such asmetoprolol, ER of 25-200 mg API, such as 50-200 mg of API, preferably50-150, such as 75-125, for example about 80 mg or about 100 mg.

Other beta-blockers, such as carvedilol may require lower dosages. Inthis case one dosage form may comprise an amount of beta blocker, suchas carvedilol, ER of 20-100 mg of API, preferably 30-80, for exampleabout 20 mg, 40 mg or about 80 mg.

The amount of tesofensine per dosage form (in the second composition) isgenerally from 0.1-1 mg API, preferably 0.2-0.8 mg, for example0.25-0.75 mg, such as 0.4-0.6 mg for example about 0.25 mg, 0.5 mg or0.75 mg.

The amount of beta blocker, such as metoprolol, IR per dosage form maybe from 5-100 mg API, for example 50-80 mg, preferably 10-75 mg, such as10-50 mg, such as 20-30 mg or 10-20 mg, for example about 5 mg, about 10mg, about 15 mg, or about 25 mg.

Thus one dosage form may comprise 50-200 mg ER beta blocker, such asmetoprolol, 5-50 mg IR beta blocker, such as metoprolol, and 0.1-1.5 mgtesofensine; for example 75-125 mg ER beta blocker, such as metoprolol,10-25 mg IR beta blocker, such as metoprolol, and 0.25-0.75 mgtesofensine; for example 75-80 mg ER beta blocker, such as metoprolol,10-15 mg IR beta blocker, such as metoprolol, and 0.25-0.75 tesofensine;for example 75-85 mg ER beta blocker, such as metoprolol, 15-25 mg IRbeta blocker, such as metoprolol, and 0.25-0.75 tesofensine; for example90-110 mg ER beta blocker, such as metoprolol, 20-30 mg IR beta blocker,such as metoprolol, and 0.25-0.75 tesofensine.

Thus one dosage form may comprise 20-100 mg ER beta blocker, such ascarvedilol, 5-40 mg IR beta blocker, such as carvedilol, and 0.1-1.5 mgtesofensine; for example 30-80 mg ER beta blocker, such as carvedilol,5-20 mg IR beta blocker, such as carvedilol, and 0.25-0.75 mgtesofensine; for example 40-80 mg ER beta blocker, such as carvedilol,10-20 mg IR beta blocker, such as carvedilol, and 0.25-0.75 tesofensine.

In one embodiment the beta blocker is metoprolol and the amount of thetwo APIs in the three phases of the current dosage form are present inthe following absolute amounts.

Metoprolol ER Metoprolol IR Tesofensine IR 50-200 mg 5-50 mg 0.1-1.5 mg75-125 mg 10-25 mg 0.25-0.75 mg 75-80 mg 10-15 mg 0.25-0.75 mg 100 mg 25mg 0.5 mg 100 mg 10 mg 0.5 mg 80 mg 20 mg 0.5 mg

In one embodiment the beta blocker is carvedilol and the amount of thetwo APIs in the three phases of the current dosage form are present inthe following absolute amounts.

Carvedilol ER Carvedilol IR Tesofensine IR 20-100 mg 5-25 mg 0.1-1.5 mg30-80 mg 5-20 mg 0.25-0.75 mg 80 mg 20 mg 0.25-0.75 mg 40 mg 10 mg 0.5mg 20 mg 5 mg 0.5 mg

Multi-Layer Dosage Form

The extended release phase may be part of a multiple layer tablet, suchas a bi or tri-layer dosage form.

In one embodiment, the dosage form comprises a tri-layer dosage unithaving an extended release (ER) phase layer with a beta blocker, such asmetoprolol or carvedilol, and one immediate release phase layer with abeta blocker, such as metoprolol or carvedilol and another immediaterelease layer with tesofensine. The ER phase contains a therapeuticallyeffective amount of the beta blocker, such as metoprolol or carvedilol,suitably in granulate form.

In other embodiments, the dosage form is a bi-layer tablet having an ERphase layer with a beta blocker, such as metoprolol or carvedilol andone immediate release layer with both the betablocker (such asmetoprolol or carvedilol) and tesofensine.

Extended Release Phase

Extended release compositions of beta blockers, such as metoprolol orpharmaceutically acceptable salts of metoprolol are known the art.Non-limiting examples of disclosures of such compositions are found in:WO 2015/004617, WO 2013/084089, WO 2013/030725, WO 2012/052834, WO2011/143420, WO 2007/09770, WO 2004/069234, WO 2007/110753, WO2007/029070, WO 2008/012346, and WO 2007/048233. Such extended releasecompositions typically involve coating the API with an extended releaselayer that provides an approximated zero-order rate of dissolution ofthe API.

In one embodiment, the extended release beta blocker, such asmetoprolol, is formulated as pellets with pharmaceutically acceptableexcipients such as for example binders, film coating polymers,plasticizers, starch, glidants, and disintegrants.

An extended release formulation of carvedilol is also known from U.S.Pat. No. 8,101,209 (Flamel Technologies).

Inert Core

In some embodiments, the pellets comprise an initial core (inert core)coated with a layer of a beta blocker, such as metoprolol or ametoprolol salt, and further coated with an extended release layer.

As used herein the term initial core refers to a pharmaceuticallyacceptable core for use in pharmaceutical formulations which core isinert.

In one embodiment there is provided a pharmaceutical composition forextended release comprising pellets coated with a beta blocker, such asmetoprolol or a metoprolol salt, wherein each coated pellet comprises a)an inert core comprising at least 50% (w/w) of soluble substance; b) adrug layer comprising the beta blocker, such as metoprolol, which layercovers the inert core; and c) a controlled release layer thereon.

In another embodiment there is provided a pharmaceutical compositionwherein the release rate of drug from the pellets part of thepharmaceutical composition comprising a tabletted or encapsulatedcomposition of a multitude of pellets is controlled by the amount or thepercentage of the initial core/spheres of the pellets. Preferably, theamount of initial core is from about 15% to about 35% by weight of thecontrolled release coated pellets before tableting or capsule filling,such as from 20-30%.

In another embodiment the inert core is strengthened by applying asub-coat on the initial core/sphere. In pharmaceutical compositionswherein pellets comprising the drug are compressed into tablets, thedrug pellets are mixed with powder excipients to form a tableting blend.However, the size of the drug coated pellets, often larger than theparticle size of the powder excipients, can cause a lack of uniformityof the tableting blend. The preferred uniformity of the tableting blendis such that the average assay of samples of the tableting blend eachweighing the equivalent of one tablet lies within the range of 90 to 110percent of the label dose and the relative standard deviation of theindividual assays is less than or equal to 5 percent. The size of thedrug pellets is therefore preferably small. When layering a large amountof drug on a small initial core a high degree of stress is exerted onthe initial core. This stress may cause attrition particularly when theinert core comprises sugar spheres. To provide a higher degree ofphysical strength of the inert core without changing the dissolutionrate of drug coated pellets, a sub-coat may be applied on an initialcore/sphere. Preferably, the amount of the sub-coat is from about 10% toabout 40% of the total weight of the sub-coated inert core, morepreferably the amount of sub-coat is from about 15% to about 30% of thetotal weight of the sub-coated inert core, most preferably the amount ofsub-coat is about 16% to about 20% of the total weight of the sub-coatedinert core.

The inert core of each of the pellets in the pharmaceutical compositionmay comprise from about 50% to about 100% (per weight) of solublesubstance. Preferably the inert core comprises from about 70% to about90% (per weight) of soluble substances. A preferred initial corecomprises a sugar sphere. Sugar spheres have been used in thepharmaceutical industry as excipients. Such sugar spheres used inpharmaceutical compositions generally contain not more than 92% ofsucrose, calculated on the dried basis, the remainder consisting ofmaize starch. Commonly sugar spheres with a core size larger than 500 μmare used. The core size of the inert cores, preferably a sugar sphere,is between about 50 μm and about 500 μm, preferably between about 100 μmand about 400 μm, more preferably from about 250 μm to about 350 μm.

The inert core may comprise an initial core/sphere that is sub-coatedwith a layer of a plasticized film coating polymer. This sub-coating ofan initial core/sphere provides physical strength to the inert core. Thefilm coating polymer may be a hydrophobic or a hydrophilic polymer, or acombination of the two. Suitable film coating polymers can be cellulosederivative polymers or polymethacrylate polymers. Further, hydrophobicpolymers or hydrophilic plasticizers, or a combination of severalplasticizers can be used to plasticize the film coating polymers. Thesecompounds of the polymeric sub-coat are mixed with solvents prior totheir application onto the initial core/sphere. Suitable solvents foruse in mixing the polymeric sub-coating compounds are selected fromethanol, isopropyl alcohol, acetone and purified water. For example amixture of ethanol, acetone and water is preferred for use in mixing amixture of the preferred sub-coating compounds EthylCellulose (as a filmcoating polymer), and plasticizers Dibyutyl Sebacate and PolyethyleneGlycol (EC, DBS and PEG).

Preferably, the initial core/sphere is a sugar sphere which is subcoated with a mixture of polymers such as cellulose derivatives e.g.ethylcellulose and triethyl citrate, polyethylene glycol, dibutylsebacate, and dibutyl phthalate, and wherein the sub-coating layer onthe initial core/sphere does not alter the release rate of the drug forthe pharmaceutical composition. A preferred sub-coat on the sugarspheres comprises ethyl cellulose as a hydrophobic film coating polymerand a combination of two or more plasticizers, at least one hydrophilicand at least one hydrophobic plasticizer. Suitable plasticizers mayinclude for example polyethylene glycols, citrate esters, dibutylsebacate, diethyl phthalate, and triacetin. Preferred plasticizers arepolyethylene glycol and dibutyl sebacate as the hydrophilic andhydrophobic plasticizers respectively. Preferably, the sub-coatcomprises about 75% to about 85% ethyl cellulose, about 10% to about 20%polyethylene glycol and about 3% to about 7% dibutyl sebacate by weightof the sub-coat. More preferably, the sub-coat comprises 80% ethylcellulose, 15% polyethylene glycol and 5% dibutyl sebacate by weight ofthe sub-coat.

Alternatively the core may be an insoluble core onto which the activeingredient has been deposited for example by spraying. It may be madefrom silicon dioxide, glass or plastic resin particles. Suitable typesof plastic material are pharmaceutically acceptable plastics such aspolypropylene or polyethylene preferably polypropylene. Such insolublecores may have a diameter in the range of 0.01-2 mm, preferably in therange of 0.05-1.0 mm and more preferably in the range of 0.1-0.7 mm.

Beta Blockers for Extended Release

In one embodiment, a beta blocker, such as Metoprolol or its acceptablepharmaceutical salt, may be applied on the inert core. No use of “Class2” solvents (as defined by the FDA) is required to apply the activepharmaceutical ingredient (API), drug, onto the inert core forming adrug coated pellet. The FDA defines “Class 2” solvents as havinginherent toxicity. The active ingredient is dispersed in water,preferably together with an acceptable binder excipient such as, but notlimited to, polyvinyl pyrrolidone, cellulose derivatives polymers, orstarch.

The beta blocker, such as metoprolol may be applied as a dispersionrather than a solution. Therefore it is preferred that the drugsubstance has physical properties that will allow a high yield inpreparing drug coated pellets. Therefore, the drug substance preferablyhas a particle size distribution such that the d(0.9) value is less thanabout 80 μm. Preferably, the d(0.9) value for the particle sizedistribution of the drug substance is less than about 50 μm, morepreferably less than about 30 μm. As a result, a concentrated dispersionfor application can be produced which may shorten the production time.

The drug coated pellets may comprise from about 40% to about 90% (perweight) of the drug layer, preferably from about 50% to about 80% (perweight), more preferably from about 55% to about 75% (per weight).

Other beta blockers, such as Carvedilol or salts thereof, may be appliedin a similar as indicated for Metoprolol.

Controlled Release Layer

The last layer applied on the pellets is a layer which controls therelease of the active pharmaceutical ingredient. Pellets that have beencoated with a controlled release layer may have a size between about 200μm and about 800 μm. Preferably, the controlled release layer coatedpellets have a size ranging from about 300 μm to about 700 μm, morepreferably from about 400 μm to about 600 μm. In addition, thecontrolled release layer may comprise water soluble and insolublecomponents. Such components may be film forming polymers andplasticizers. For example, a film comprising a polymeric layer may beapplied onto the drug coated pellets.

In the following three different types of extended release coatings aredescribed.

First Extended Release Coating.

In one embodiment the extended release film coat comprises i) an acrylicpolymer ii) a surfactant and iii) sodium stearyl fumarate, wherein thefilm coat has been deposited from a water containing liquid.

Typically a film coating composition comprises

a) 25 to 35% by weight of an acrylic polymer dispersionb) 0.1 to 4% by weight of a surfactantc) 0.1 to 4% sodium stearyl fumarate andd) a water-containing liquid to 100%.

In one embodiment there is provided film coatings which are suitable forgiving extended release. Suitably the acrylic polymer used in this casecomprises homogeneous particles wherein the polymer or copolymer hasT_(g)<room temperature in aqueous dispersion but has T_(g)>roomtemperature in the dry state. Suitable polymers comprise acrylic acidand esters thereof particularly the methyl, ethyl, propyl and butylesters; and methacrylic acid and esters thereof particularly the methyl,ethyl, propyl and butyl esters. Particularly preferred polymers arethose provided under the tradenames Eudragit L30D® (Rohm Pharma) orEudragit FS30D® (Rohm Pharma). Optionally further anti-tacking agentsmay be required.

Suitably the amount of the acrylic polymer in the film coatingcomposition is in the range of 15 to 50% by weight. Preferably theamount of the acrylic polymer in the film coating composition is in therange of 20 to 40% by weight. More preferably the amount of the acrylicpolymer in the film coating composition is in the range of 25 to 35% byweight.

Suitably the surfactant is one of the following: a nonionic surfactant,like sorbitan esters (Span series); polysorbates (Tween series);polyoxyethylated glycol monoethers (like the Brij series);polyoxyethylated alkyl phenols (like the Triton series or the Igepalseries); alkyl glucosides (e g dodecylmaltoside); sugar fatty acidesters (e g sucrose laurate); saponins; etc: or mixtures thereof;ampholytic surfactants, like betaines; anionic surfactants, likesulphated fatty alcohols eg sodium dodecylsulphate SDS; sulphatedpolyoxyethylated alcohols; others like dioctyl sulphosuccinate; bilesalts (e g dihydroxy bile salts like sodium deoxycholate, trihydroxybile salts like sodium glycocholate, etc); fusidates (e g sodiumdihydrofusidate); etc cationic surfactants, like ammonium compounds;soaps, fatty acids, and lipids and their salts, like alkanoic acids; (eg octanoic acid, oleic acid); monoglycerides (eg monolein),phospholipids which are neutral or positively or negatively charged (egdialkyl phosphatidylcholine, dialkyl phosphatidylserine, etc); etc; morepreferably the surfactant is a nonionic surfactant. Most preferably thesurfactant is nonoxynol 100.

Suitably the amount of the surfactant in the film coating composition isin the range of 0.05 to 8% by weight. Preferably the amount of thesurfactant in the film coating composition is in the range of 0.1 to 6%by weight. More preferably the amount of the surfactant in the filmcoating composition is in the range of 0.5 to 4% by weight.

In a most preferred embodiment the acrylic polymer and the surfactantare provided by Eudragit® NE30D in compositions, a film coats orformulations defined previously.

Suitably the amount of the sodium stearyl fumarate in the film coatingcomposition is in the range of 0.05 to 8% by weight. Preferably theamount of sodium stearyl fumarate in the film coating composition is inthe range of 0.1 to 6% by weight. More preferably the amount of sodiumstearyl fumarate in the film coating composition is in the range of 0.5to 4% by weight.

Suitably the water-containing liquid comprises water and a watermiscible organic liquid for example lower alkanols e.g. ethanol,propanol or isopropanol. From a safety point of view is preferred thatthe proportion of the organic is kept to a minimum but small amounts aretolerable for example in the range of 0 to 20% by volume. Preferably theliquid is water.

The film-coating composition is particularly suitable for use as anaqueous film-coating composition wherein the film-coat is applied usingwater as the liquid. When the liquid is water the latex is preferably apoly(ethylacrylate-co-methylmethacrylate) copolymer, for exampleEudragit NE30D® (Rohm Pharma). This process is particularly advantageousas it negates the need to use environmentally unacceptable organicsolvents, some of which also present processing problems due to theirinflammablility, while also eliminating many of the problems experiencedwith aqueous coatings described above.

Second Extended Release Coating

Alternatively, the film may comprise at least one film coating polymerand can be plasticized with one or more plasticizers. These plasticizersmay differ from each other in their degree of solubility(hydrophobicity/hydrophilicity). By changing the ratio between theplasticizers and the film coating polymer, or the ratio between thedifferent plasticizers (if more than one is used), one can control therate of the release of the drug from the pellets. The controlled releaselayer of the beta blocker ER may comprise a hydrophobic film coatingpolymer such as for example ethylcellulose and a combination of at leasttwo plasticizers, at least one hydrophilic and one hydrophobicplasticizer, for example polyethylene glycol and dibutyl sebacate.Preferably, the ratio of hydrophobic to hydrophilic plasticizer in thecontrolled release layer of the pharmaceutical composition is from 3:1to 1:3, more preferably the ratio is 1:1.

Furthermore, the controlled release layer may comprise at least about70% water insoluble compounds (per weight of the controlled releaselayer). Preferably, the controlled release layer comprises at leastabout 80% and more preferably at least about 90% water insolublecompounds (per weight of the controlled release layer). Suitable waterinsoluble compounds are for example cellulose derived polymers. Thesecontrolled release layer compounds are mixed with solvents prior totheir application onto the drug coated pellets. Suitable solvents foruse in mixing the controlled release layer compounds are selected fromethanol, isopropyl alcohol, acetone and purified water. A mixture ofethanol, acetone and water is preferred for use in mixing the controlledrelease layer compounds especially where the controlled release layercompounds are a mixture of ethylcellulose, dibutyl sebacate andpolyethylene glycol.

The method of preparing the beta blocker ER component may comprisesub-coating an initial core/sphere forming an inert core. Sub-coating aninitial core/sphere comprises mixing a film coating polymer with one ormore plasticizers in a solvent forming a coating mixture. Such mixturemay be a solution, suspension or slurry for applying a coating layer ona surface. The coating mixture is applied to the initial core/sphereforming a sub-coated initial core/sphere which is used as an inert core.The film coating polymer may be a hydrophobic or a hydrophilic polymer,or a combination of the two. Suitable film coating polymers can becellulose derivative polymers or polymethacrylate polymers, preferablyethylcellulose. The amount of ethylcellulose is preferably from about75% to about 85% more preferably about 80% of the total amount of theweight of the sub-coat. Further, hydrophobic polymers or hydrophilicplasticizers, or a combination of several plasticizers can be used toplasticize the film coating polymers. These compounds of the polymericsub-coat are mixed with solvents prior to their application onto theinitial core/sphere. Suitable solvents for use in mixing the polymericsub-coating compounds are selected from ethanol, isopropyl alcohol,acetone and purified water. A mixture of ethanol, acetone and water ispreferred for use in mixing the polymeric sub-coating compounds.

Suitable plasticizers for use in sub-coating an initial core/sphere areselected from polyethylene glycol, dibutyl sebacate, and dibutylphthalate. Preferred plasticizers are polyethylene glycol and dibutylsebacate as the hydrophilic and hydrophobic plasticizers respectively.Preferred amounts of plasticizers used in the method are about 10% toabout 20% polyethylene glycol and 3% to about 7% dibutyl sebacate byweight of the sub-coat. More preferably, about 15% polyethylene glycoland 5% dibutyl sebacate as plasticizer.

For the extended release coat, the amount of ethylcellulose ispreferably from about 75% to about 85% more preferably about 80% of thetotal amount of the weight of the coat. Suitable plasticizers for use inthe ER-coating are selected from polyethylene glycol, dibutyl sebacate,and dibutyl phthalate. Preferred plasticizers are polyethylene glycoland dibutyl sebacate as the hydrophilic and hydrophobic plasticizersrespectively. Preferred amounts of plasticizers used in the method areabout 5% to about 20% polyethylene glycol and dibutyl sebacate by weightof the ER-coat. More preferably, about 10% polyethylene glycol and 10%dibutyl sebacate as plasticizer.

In one embodiment, a metoprolol ER tablet comprises:

Percent total Material Weight pellet weight Sub-coated pellets Sugarspheres (250-355 μm) 598.00 22.3 Ethyl cellulose 7 cps 92.00 3.4Polyethylene glycol 400 17.25 0.6 Dibutyl sebacate 5.75 0.2 Drug layerMetoprolol succinate 1092.50 40.9 Polyvinyl pyrrolidone povidone 27610.3 (PVP K-30) Controlled release film layer Ethyl cellulose 100 cps473.8 17.7 Polyethylene glycol 400 59.23 2.2 Dibutyl sebacate 59.23 2.2

In a preferred method of preparing the beta blocker ER part of thecomposition, the method comprises the following steps; a) providingsugar spheres as initial cores; b) coating the sugar spheres with asub-coat comprising mixing a film of a hydrophobic polymer, a soluble(hydrophilic) plasticizer, and an insoluble (hydrophobic) plasticizerwith a solvent mixture of e.g. acetone, ethanol 95%, and water andspraying the mixture onto the sugar spheres to create a sub-coat on thesugar spheres resulting in an inert core; c) coating the sub-coatedsugar spheres (inert cores) with a drug layer comprising mixing thedrug, such as metoprolol succinate, and a binder, preferably povidone(PVP K-30) with preferably water, forming an aqueous dispersion andapplying the dispersion onto the sub-coated pellets (inert cores)forming drug coated pellets; d) applying a third layer on the drugcoated pellets comprising dissolving a hydrophobic film coating polymer,an hydrophilic plasticizer and an hydrophobic plasticizer in a solventmixture of e.g. acetone, ethanol 95%, and water forming a mixture andspraying the mixture onto the drug coated pellets to create controlledrelease drug coated pellets; e) mixing the controlled release drugcoated pellets with a powder mixture of one or more excipients forming afinal blend; f) compressing the final blend into tablets or filling thefinal blend into capsules; and g) optionally film coating the tabletsfor cosmetic purposes.

In this method the hydrophobic polymer is preferably ethyl cellulose(EC), the soluble/hydrophilic plasticizer is preferably polyethyleneglycol (PEG), and the insoluble/hydrophobic plasticizer is preferablydibutyl sebacate (DBS). Further, in preparing a mixture for coating thesugar spheres with a sub-coat, and the drug coated pellets with acontrolled release layer, ethyl cellulose is preferably first dissolvedin acetone and ethanol 95%, then PEG and DBS are added, followed byadding water and mixing the solution till it is homogenized. Preferably,the spraying of a solution or dispersion onto sugar spheres or drugcoated pellets in the method uses a fluidized bed coater with a Wursterinsertion. Furthermore, the binder, used in coating the sub-coated sugarspheres with a drug layer, facilitates binding of the drug to the inertcore of sub-coated sugar spheres. Moreover, in this method the ratio ofpowder mixture to controlled release drug coated pellets in the finaltableting blend is preferably from about 20% to about 60% (by weight),more preferably from about 30% to about 50% (by weight), most preferablyfrom about 35% to about 45% (by weight). As a result a uniform finaltableting blend and tablets are produced.

Third Extended Release Coating

An extended release phase may comprise at least one high viscosityhypromellose (HPMC) ingredient. HPMC is a water soluble matrix-formingpolymer used to provide an extended release effect of metoprolol. Theviscosity of the HPMC used in the ER phase may be up to 100.000centipoise such as in the range of about 3500-6000 cps.

An extended release layer with a therapeutically effective amount of abeta blocker, such as metoprolol or carvediol, can be made with highviscosity hypromellose alone.

In other embodiments, the extended release layer comprises atherapeutically effective amount of a beta blocker, such as metoprololor carvediol, at least one high viscosity hypromellose, at least onebinding agent, a low viscosity hypromellose, at least one modifiedstarch, and optionally one or more other pharmaceutically acceptableintragranular components including but not limited to a secondpharmaceutically acceptable active ingredient, other pharmaceuticallyacceptable excipients and/or adjuvants. In one embodiment, the ratio ofhigh-viscosity hypromellose to low viscosity hypromellose is about 3.3to about 0.85. In another embodiment the ratio of high to low is about3:1.

Suitably, the viscosity of the low viscosity hypromellose is in therange of about 10-30 centipoises. In another embodiment the lowviscosity is about 15 centipoises.

The amount of at least one binding agent in the extended release phaseof a bilayer tablet may be from about 0.5% to about 3% w/w. In oneembodiment there are at least two binding agents present in the ERphase. Suitably the amount of at least one modified starch in theextended release phase of the bilayer tablet is from about 0.5% to about3% w/w. In one embodiment, the amount of modified starch is about 1% w/wof the ER phase. In one embodiment there are at least two modifiedstarches present in the ER phase. Suitably, the modified starch ispre-gelatinized.

Suitably, the amount of the high viscosity hypromellose present in theextended release phase is from about 3%> to about 7%> of the extendedrelease phase formulation weight. In another embodiment, the amount ofhigh viscosity hypromellose is from about 4% to about 6%. In still otherembodiments, an amount of >20% hypromellose is used in the extendedrelease phase.

In yet another embodiment the amount of high viscosity HPMC is presentin an amount of about 5% w/w extended release phase formulation weight.

Suitably, the amount of the low viscosity hypromellose present in theextended release phase is from about 0.5% to about 3% of the extendedrelease phase formulation weight. In another embodiment, the amount oflow viscosity hypromellose is from about 1% to about 2% of the extendedrelease phase formulation weight.

Alternatively, the total amount of cellulosic derivatives of HPMCpresent in the ER granulate range from about 3% to about 10% by weightof the total amount of extended release components. This encompassesboth the high and the low viscosity HPMC's.

In one embodiment the ER phase comprises metoprolol, povidone,pre-gelatinized corn starch, and a high and low viscosity HPMC.

In one embodiment the ER phase comprises carvedilol, povidone,pre-gelatinized corn starch, and a high and low viscosity HPMC.

Tablets and Capsules

The film coated beads or spheres may be provided in sachets orformulated as a capsule, for example a hard gelatin capsule, orcompressed to form tablets using known methods with the optionaladdition of other pharmaceutically acceptable additives and with theaddition of the beta blocker IR and tesofensine components hereindescribed. Coated beads to be compressed into a tablet are obtained byconventional techniques known to those skilled in the art.

Also, during this process suitable other agents can be added. Forexample, during the tabletting step suitable fillers, egmicrocrystalline cellulose, lactose monohydrate, talc. sodium stearylfumarate etc can be utilised to give acceptable compressioncharacteristics of the formulation, e g hardness of the tablet.

These additives can be granulated in one of the conventional granulationmethods. However, preferably there is provided a set of additives, forexample a powder mixture that can be directly compressed into tablets.Such powder mixture serves as a filler, cushioning, disintegrant,glidant, and lubricant mixture. Furthermore, the ratio of controlledrelease drug coated pellets to additives in the final (e.g. tableting)blend of the present pharmaceutical composition is of particularimportance to prepare a uniform product e.g. tablets.

To prepare a uniform product, preferably at least 50% (by weight) of thepowder mixture may have particle sizes between about 30 μm to about 800μm, preferably from about 80 μm to about 600 μm, more preferably fromabout 100 μm to about 300 μm. More preferably, at least 65% (by weight)of the powder mixture has particle sizes between about 30 μm to about800 μm, preferably from about 80 μm to about 600 μm, more preferablyfrom about 100 μm to about 300 μm. Most preferably, at least 80% (byweight) of the powder mixture has particle sizes between about 30 μm toabout 800 μm, preferably from about 80 μm to about 600 μm, mostpreferably from about 100 μm to about 300 μm.

Furthermore, the amount of controlled release drug coated pellets in thefinal tableting blend is preferably from about 20% to about 60% (byweight) in order to prepare such uniform product. More preferably, theamount of controlled release drug coated pellet in the final tabletingblend is from about 30% to about 50% (by weight), most preferably fromabout 35% to about 45% (by weight).

Suitable powder mixtures comprise, but are not limited to, mixtures oftwo or more of the following compounds; Starlac(R) (a spray-driedcompound consisting of 85% alpha-lactose monohydrate and 15% maizestarch dry matter available from Meggle), Cellactose(R) (a spray-driedcompound consisting of 75% alpha-lactose monohydrate and 25% cellulosepowder dry matter available from Meggle), Parteck(R) (A DirectlyCompressible Sorbitol available from Merck KGaA), Crospovidone, SiliconDioxide, Magnesium Stearate, Talc, Zinc Stearate, PolyoxyethyleneStearate, Stearic Acid, sodium stearyl fumarate Cellulose derivatives,microcrystalline cellulose and lactose monohydrate.

If the dosage form is a bi- or tri-layer tablet, the immediate releaselayer(s) may be compressed directly on a previously partly compressedextended release layer, or alternatively, the extended release layer maybe compressed onto previously partly compressed immediate releaselayer(s).

The compositions can be formulated by conventional methods of admixturesuch as granulating, blending, filling and compressing. For example,tablets can be produced by a wet granulation process, where theimmediate release phase and extended release phase are separatelyprepared. Suitably, for either the immediate release or extended releasephase, the active drug substance and excipients are screened and mixedin a high shear mixer granulator or fluid bed dryer. The blend isgranulated by the addition of a granulating solution (typically purifiedwater, disintegration agent dissolved/dispersed in purified water, ordrug dissolved/dispersed in purified water or a suitable solvent)sprayed into the high shear mixer granulator or fluid bed dryer. Ifdesired wetting agents e.g., surfactants can be added. The resultinggranules (optionally pelletized) are dried usually with residualmoisture of 1-5% by tray, fluid bed or microwave drying techniques. Thedried granules are milled to produce a uniform particle size, thegranules are blended with extragranular excipients as necessary,typically a lubricant and glidant (e.g., magnesium stearate, silicondioxide). The separately prepared immediate release and extended releasegranules can then be compressed together using a rotary tablet press(such as a bilayer tablet press) if desired. If the dosage form is asingle layer tablet, then the extended release granules are admixed withthe immediate release extragranular components and compressed togetherusing a rotary tablet press, etc. These resulting tablets can all becoated in a pan coater typically with a 1-5% aqueous film coat, followedby a wax polishing.

Alternatively tablets can be produced by a direct compression process.Suitably the active drug substance and excipients for the immediaterelease and extended release phases are separately screened and mixed ina suitable blender e.g., a cone, cube or V-blender. Other excipients areadded as necessary, and further blended. The separately preparedimmediate release and extended release phases can be combined andcompressed together using a rotary tablet press as hereinbeforedescribed. The resulting tablets can be coated in a pan coater.

Tablets can also be prepared by using both methods of wet granulationand direct compression. For example the extended release phase can beprepared by wet granulation as described herein, while the immediaterelease phase can be prepared by blending the excipients for directcompression. The two phases can then be combined and compressed togetheras hereinbefore described.

Immediate Release Phase(s)

The immediate release phase(s) may be prepared by combining a directlycompressible commercially available grade of the beta blocker, such asmetoprolol, and tesofensine with a lubricant, and one or moredisintegrating agents if necessary or desired. Binders and otherexcipients and/or adjuvants may be included in the immediate releaselayer(s), also if necessary or desired. The beta blocker and tesofensinein the immediate release layer may be combined with a modified starchsuch as a pre-gelatinized starch, e.g., corn starch, polyethyleneglycol, and a disintegrant, or super disintegrant such as croscarmellosesodium or Explotab®, a binder such as methylcellulose or hypromellosepolymer, plasticizer, pigment and a lubricant.

The immediate release phases may comprise two different layers of thebeta blocker and tesofensine, respectively. Alternatively, the immediaterelease phases may be combined into one and the same layer. Theimmediate release phases may also be formulated into an extragranularphase of a tablet or be granulated into one or two different immediaterelease granules. For tesofensine, the preferred formulation is agranulation of tesofensine compared to direct compression of tesofensineas the dose is relatively low.

Monolith Dosage Form

In one embodiment, there is only a single layer tablet having anextended release intra-granular phase and two immediate releaseextra-granular phases. The extended release phase will be comprised ofan intra-granular component of the beta blocker and excipients asdescribed above. These components form the ER granulate. The ER blendcould be made into pellets and compressed accordingly with theextra-granular immediate release blend.

A suitable extra-granular component or phase, i.e., the immediaterelease phases, may be prepared by combining a directly compressiblecommercially available grade of a beta blocker, such as metoprolol, andtesofensine citrate with a lubricant, and one or more disintegratingagents if necessary or desired. As mentioned above for tesofensine thepreferred process is to prepare a granulate of tesofensine beforecompression. Binders and other excipients and/or adjuvants may beincluded in the extra-granular phase if necessary or desired.Alternatively, an extra-granular component can be prepared by combiningthe beta blocker, such as metoprolol, and tesofensine with a modifiedstarch, such as a pre-gelatinized starch, e.g., corn starch, adisintegrant or super disintegrant, such as croscarmellose sodium, abinder and a lubricant.

Excipients

The present compositions may include components that functions as abinder or binding agent. Suitably, the binding agent may comprise afirst binding agent and a second binding agent. Suitable binding agentsfor use herein include conventional binding agents used in the art suchas gelatin, starches, povidone, polymers and cellulose derivatives orcombinations thereof.

Suitably, the starch, is of vegetable origin, such as corn (or maize)starch, modified corn starch, wheat starch, modified wheat starch,potato starch, or pre-gelatinized starch e.g., available commercially asStarch 1500 G or Prejel; or a combination of two or more thereof.

If the binding agent includes a cellulosic derivative such ashydroxypropyl cellulose (HPC) (of low to medium viscosity) e.g., as maybe available commercially under the brand name Klucel® from the Aqualondivision of Hercules Inc., Dow Chemical Company e.g., Klucel G F, KlucelJ F, Klucel L F and Klucel E F; microcrystalline cellulose (MCC),carboxymethylcellulose (MC), sodium carboxymethylethyl cellulose; or acombination of two or more thereof. Combinations of a cellulosicderivative with other binding agents noted above are also envisaged.Generally the total amount of cellulosic derivatives present in thegranulate are in an amount ranging from about 3% to about 10% by weightof the extended release components. It is recognized in the art thatcertain cellulosic derivatives, such as hypromellose, will have varyingroles in a formulation, depending upon the amount used. For examplehypromellose (low or medium viscosity) may function as a binding agent,a coating agent, or as a matrix forming agent.

While a binding agent is present as an intra-granular component, it isrecognized that a modest amount of binding agent e.g., up to about anadditional 3.0%>-10.0% by weight of the intra-granular binding agentcontent of the composition, may also be present extra-granularly.

In one embodiment, suitably the starch is pre-gelatinized starch.Pre-gelatinized starch is a starch that has been chemically and/ormechanically processed. Typically pre-gelatinized starch contains 5% offree amylase, 15% of free amylopectin, and 80% unmodified starch.Pre-gelatinized starch may be obtained from corn (or maize), potato orrice starch.

The granulate provides an intimate admixture of a combination ofingredients and may then be mixed with one or more pharmaceuticallyacceptable extra-granular components of the composition i.e., with anypharmaceutically acceptable ingredient e.g., a diluent, flavor,sweetening agent, binder, disintegrant, glidant, lubricant,anti-adherent, anti-static agent, anti-oxidant, desiccant, or a secondpharmaceutically acceptable active agent. It is recognized that thesesame ingredients may be present both as an intra-granular and as anextra-granular ingredient.

As noted above there are other inactive ingredients that may optionallybe employed in relatively small quantities, which include lubricants,flow agents, and binders that facilitate compression.

Suitable disintegrating agents include a non-super disintegrant, a superdisintegrant or a combination of both. Suitable non-super disintegrantsinclude conventional disintegrants such as starch (corn or maize),pre-gelatinized starch e.g., Starch 1500 G, clays (e.g. VEEGUM(Vanderbilt Minerals, LLC) or Bentonite (an absorbent aluminiumphyllosilicate clay consisting mostly of montmorillonite)),microcrystalline cellulose, cellulose or powdered cellulose. It isrecognized in the art, that some excipients may perform more than onerole in a given pharmaceutical formulation. For example certainexcipients, e.g., starches including pre-gelatinized starch, andmicrocrystalline cellulose (hereinbefore identified as binding agents)function as both binders and disintegrants.

A “super disintegrant” represents a class of disintegrating agent whichmay generally be used in lower amounts in pharmaceutical preparations,as compared to conventional disintegrants. Examples of superdisintegrants include sodium starch glycolate, the sodium salt ofcarboxymethyl starch, modified cellulose and cross-linked polyvinylpyrrolidone. Sodium starch glycolate is available commercially under thetrade names Explotab® (Edward Mendell Co. JRS Pharma), Primojel®(Generichem Corp; DFE Pharma) and Tablo® (Blanver, Brazil). An exampleof modified cellulose includes croscarmellose sodium, the sodium salt ofcarboxymethyl cellulose. Croscarmellose sodium is available commerciallyunder the trade names AcDiSol® (FMC Corp.), Nymcel ZSX® (Nyma,Netherlands), Primellose® (Avebe, Netherlands), Solutab® (Blanver,Brazil). An example of a cross-linked polyvinyl pyrrolidone includescrospovidone, and is commercially available under the trade namesKollidon CL® or Kollidon CL-M (Basf Corp.), and Polyplasdone XL® (ISPCorp; Ashland). A suitable super disintegrants includes croscarmellosesodium or sodium starch glycolate (e.g. Explotab® (JRS Pharma)) or acombination thereof. A super disintegrant may be used extragranularly,in an amount ranging from about 0.5% to about 5.0% by weight of thecomposition. Suitable preservative or antimicrobial agents for useinclude potassium sorbate or a paraben, i.e., one or more hydroxybenzoic acid esters e.g., methyl, ethyl, propyl or butyl, suitablysingularly or as mixtures. Parabens are commercially available under theNipa® brand name, e.g., Nipasept® sodium (Aako BV, The Netherlands).

Suitable lubricants include magnesium, calcium or sodium stearate,stearic acid or talc that may be added in suitable amounts. In oneembodiment the lubricant is magnesium stearate.

Suitable flow agents include silicon dioxide (e.g. Cab-O-Sil® (CabotCorporation), Syloid™ (W.R. Grace & Co.)) and colloidal silicon dioxide(Aerosil® (Evonik Resource Efficiency GmbH)), that may be added in anamount from about 0.5% to about 1% by weight.

The compressed tablet may further comprise a film coat e.g.,hypromellose or polyvinyl alcohol-part.hydrolised (PVA). Suitably thefilm coat is a transparent film coat e.g., a dye, although an opaquefilm coat e.g., as obtained when using a film coat in combination withan opacifier or a pigment such as titanium dioxide or a lake may also beused. For example one commercially available film coat is an Opadry®coating system from Colorcon.

Medical Use

The composition as described herein is useful as a medicament, e.g. forthe treatment, prevention or alleviation of obesity and/or an obesityassociated disorder.

Due to the particular combination of extended and immediate releaseforms of a beta blocker in combination with tesofensine as describedherein the composition of the present disclosure effectively alleviatescardiovascular side-effects of tesofensine while maintaining thetherapeutic efficacy of tesofensine.

In one embodiment the composition of the present disclosure is for useas a medicament.

In one embodiment the composition of the present disclosure is for usein the treatment of obesity.

Obesity is defined herein as a medical condition in which excess bodyfat has accumulated to the extent that it may have an adverse effect onhealth, leading to reduced life expectancy and/or increased healthproblems in general. Thus, in one embodiment the subject to be treatedwith the composition of the present disclosure is obese.

Body mass index (BMI) is a measure which compares weight and height.People are generally considered overweight or pre-obese if the BMI isbetween 25 and 30 and obese if the BMI is over 30. Morbidly obesesubjects have a BMI over 35.

In one embodiment the subject has a BMI above 25 kg/m², such as above 30kg/m², for example above 35 kg/m², such as above 40 kg/m².

In one embodiment the subject has a BMI above 30 kg/m².

In one embodiment the subject has a BMI above 35 kg/m².

In one embodiment the composition of the present disclosure is for usein the treatment of an obesity associated disorder, such as a disease ordisorder selected from the group consisting of diabetes, metabolicsyndrome, dyslipidemia, atherosclerosis, drug-induced obesity,overeating disorders, bulimia nervosa, binge eating disorder, compulsiveover-eating, impaired appetite regulation, nonalcoholic fatty liverdisease (NAFLD) and nonalcoholic steatohepatitis (NASH).

In one embodiment the composition of the present disclosure is for usein the treatment of diabetes, such as type 1 diabetes, type 2 diabetes,prediabetes and gestational diabetes. Preferably, the diabetic subjectis obese.

In one embodiment the composition of the present disclosure is for usein the treatment of type 1 diabetes.

In one embodiment the composition of the present disclosure is for usein the treatment of type 2 diabetes.

In one embodiment the composition of the present disclosure is for usein the treatment of prediabetes.

In one embodiment the composition as described herein leads to analleviation or improvement of diabetic complications.

Type 1 diabetes (diabetes mellitus type 1) is a form of diabetes thatresults from the autoimmune destruction of the insulin-producing betacells in the pancreas. In type 1 diabetes, hypertension may reflect theonset of diabetic nephropathy.

Type 2 diabetes is a metabolic disorder that is characterized byhyperglycemia in the context of insulin resistance and a relative lackof insulin. Type 2 diabetes makes up about 90% of cases of diabetes,with the other 10% due primarily to diabetes mellitus type 1 andgestational diabetes. Obesity is thought to be the primary cause of type2 diabetes in people who are genetically predisposed to the disease.

Pre-diabetes is used interchangeably herein with intermediatehyperglycaemia. Intermediate hyperglycaemia is a biochemical state inwhich a person has glucose levels above the normal range, but does notyet meet the criteria for a diagnosis of diabetes. The primary aim ofmanagement of intermediate hyperglycaemia is to prevent progression todiabetes.

A pre-diabetic subject may have one or more of impaired fastingglycaemia (IFG) and/or impaired glucose tolerance (IGT) and/or elevatedglycated haemoglobin (HbA_(1c)) levels.

Weight loss can prevent progression of pre-diabetes into diabetes andcan also markedly improve clinical symptoms of type 2 diabetes. Thus,weight loss is an attractive treatment strategy for pre-diabeticsubjects and subjects suffering from type 2 diabetes.

In one embodiment the subject is an obese, pre-diabetic human. In oneembodiment the subject is an obese subject suffering from type 2diabetes.

Gestational diabetes is a condition in which women without previouslydiagnosed diabetes exhibit high blood glucose levels during pregnancy(especially during their third trimester). Gestational diabetes iscaused when insulin receptors do not function properly.

The WHO diabetes diagnostic criteria are shown in the table below.

2 hour glucose* Fasting glucose HbA_(1c) Condition mmol/l (mg/dl) mmol/l(mg/dl) mmol/mol (DCCT %) Normal <7.8 (<140) <6.1 (<110)  <42 (<6.0) Impaired fasting <7.8 (<140) ≥6.1(≥110) 42-46 (6.0-6.4) glycaemia & <7.0(<126) Impaired glucose ≥7.8 (≥140) <7.0 (<126) 42-46 (6.0-6.4)tolerance Diabetes mellitus ≥11.1 (≥200)  ≥7.0 (≥126) ≥48 (≥6.5) *Venousplasma glucose 2 hours after ingestion of 75 g oral glucose load

The subject benefitting from treatment with the composition of thepresent disclosure may also be a subject suffering from anobesity-associated disorder or condition, such as one selected from thegroup consisting of diabetes, metabolic syndrome, dyslipidemia,atherosclerosis, drug-induced obesity, overeating disorders, bulimianervosa, binge eating disorder, compulsive over-eating, impairedappetite regulation, nonalcoholic fatty liver disease (NAFLD) andnonalcoholic steatohepatitis (NASH).

In one embodiment the composition of the present disclosure is for usein the treatment of metabolic syndrome, such as for the treatment of anobese subject suffering from metabolic syndrome.

In one embodiment the composition of the present disclosure is for usein the treatment of fatty liver disease, such as nonalcoholic fattyliver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Thesubject suffering from NAFLD or NASH is preferably obese.

In one embodiment, the composition of the present disclosure is for usein the treatment of nonalcoholic fatty liver disease (NAFLD).

In one embodiment, the composition of the present disclosure is for usein the treatment of nonalcoholic steatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD) is a cause of a fatty liver,occurring when fat is deposited in the liver (steatosis) due to othercauses than excessive alcohol use. NAFLD is the most common liverdisorder in Western industrialized nations. NAFLD is associated withinsulin resistance and metabolic syndrome (obesity, combinedhyperlipidemia, diabetes mellitus (type II) and high blood pressure).Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD,and is a major cause of cirrhosis of the liver. NASH is a state in whichthe steatosis is combined with inflammation and fibrosis(steatohepatitis).

In one embodiment the composition of the present disclosure is for usein a method of decreasing liver fat and/or visceral adiposity. Reductionof liver fat and/or visceral adiposity has been shown to be effective inthe treatment of fatty liver disorders. Tesofensine significantlydecreases waist circumference and sagittal diameter (Astrup et al.,2008, Lancet 372: 1906-13); hence tesofensine is capable of reducingvisceral adiposity.

The composition of the present disclosure is preferably administered toa subject in need thereof once a day. However, in certain embodiments,the composition may be administered more than once a day, such as twicea day or alternatively less than once a day, such as once every secondor third day depending on the specific formulation and concentration ofthe individual components of the composition.

The subject treated is preferably a human, such as an adult human aged18 or older.

In one embodiment the present disclosure relates to use of thecomposition as disclosed herein in the manufacture of a medicament forthe treatment of diabetes, obesity or an obesity associated disorder.

The following non-limiting Examples illustrate the advantageousproperties of the compositions.

EXAMPLES Example 1

Take controlled release Metoprolol succinate pellets produced asdescribed in WO 2007/097770 with a potency of 51.19% Metoprololsuccinate (corresponding to 53.88% Metoprolol tartrate) and mix withmicrocrystalline cellulose, lactose monohydrate, croscarmellose sodiumand magnesium stearate. The mix is compressed to tablets on a rotarytablet press, each tablet with a tablet weight of 400 mg and size 7×14mm each holding 100 mg Metoprolol tartrate equivalents. Tablets willrelease the drug in a zero order release rate.

Metoprolol succinate pellets 371.2 Microcrystalline cellulose 240.0Lactose monohydrate 164.8 Croscarmellose sodium 16.0 Magnesium stearate8.0 Total 800.0

Metoprolol 100 mg ER tablets (containing 95 mg Metoprolol succinate) arefilm coated in a perforated drum coater with an aqueous film containingTesofensine citrate. Film composition is given in the table. 125 mg offilm solution is applied for each tablet corresponding to an increase intablet weight of approx. 2.2%. Spraying conditions are controlled to anoutlet air temperature of 40-45° C.

Methocel E 15 12.0 Polyethylene glycol 6000 1.2 Tesofensine citrate 0.8Water 186.0 Total 200.0

The sub coated Metoprolol tablets are further coated with the finalcoating solution given in the next table. 250 mg of film solution isapplied for each tablet corresponding to an increase in tablet weight ofapprox. 16.0%. Spraying conditions are controlled to an outlet airtemperature of 43-48° C. The final product contains 100 mg of ERmetoprolol and 25 mg of IR metoprolol.

OPADRY ® II Complete Film 50.0 Coating System 85F 18422 White Metoprololsuccinate 28.5 Water 221.5 Total 300.0

Example 2

As example 1, but with the Metoprolol film as sub coating and theTesofensine coating as final coating.

Example 3

As example 1, but using Metoprolol controlled release pellets asdescribed in U.S. Pat. No. 7,959,947, example 3 by AstraZeneca.

Example 4

Metoprolol pellets are prepared by mixing Metoprolol succinate withmicrocrystalline cellulose and adding water in a high shear mixer untilproper moistening is achieved. The wet mass is extruded through a Bepexextruder and the form strings are rolled to squares on a spheronizer.The resulting pellets of about 1 mm in diameter are dried in a fluid-bedat 60° C. inlet air temperature. The Metoprolol pellets are film coatedin a fluid-bed with bottom spray with a film to control the releasepattern. Approx. 5% weight increase is anticipated.

Metoprolol succinate 311 g Microcrystalline cellulose 289 g Water 200 gTotal 800.0 Ethylcellulose 7 cps 6.75 g Methocel E 15 0.75 g Ethanol 96%69.375 g Water 23.125 Total 100.0

Core tablets are produced from the batch composition in example 1 with acore tablet weight of 400 mg. Sub coating and final coating are appliedas described in example 1. The final product is a tablet with 100 mg ofER metoprolol and 25 mg of IR metoprolol.

Example 5

Tesofensine citrate and microcrystalline cellulose are mixed for 20minutes. Metoprolol succinate, rest of the microcrystalline celluloseand silicon dioxide, colloidal are mixed in for another 20 minutes.Controlled release Metoprolol pellets as described in example 1 areadded to the blend and mixed with for 20 minutes. The blend is filledinto hard gelatine capsules size 1.

Metoprolol succinate  23.75 g Tesofensine citrate  0.50 gMicrocrystalline cellulose  88.65 g Silicon dioxide, colloidal  1.50 gControlled release Metoprolol 185.60 g pellets 53.88% Total   300 g

The final product is a gelatine capsule with 100 mg of ER metoprolol and25 mg of IR metoprolol.

Example 6

Metoprolol ER tablet with separate film coatings of Tesofensine andmetoprolol IR.

Metoprolol 100 mg ER tablets from example 1 (containing 95 mg Metoprololsuccinate) were film coated in a perforated drum coater with an aqueousfilm containing Tesofensine citrate. Film composition is given in thetable. 370.4 mg of film solution was applied for each tabletcorresponding to an increase in tablet weight of approx. 4.2%. Sprayingconditions were controlled to an outlet air temperature of 45-50° C.

Methocel E 15 8.0 Polyethylene glycol 6000 0.8 Tesofensine citrate 0.27Water 190.93 Total 200.0

The sub coated Metoprolol tablets were further coated with the finalcoating solution given in the next table. 312.5 mg of film solution wasapplied for each tablet corresponding to an increase in tablet weight ofapprox. 15.7%. Spraying conditions were controlled to an outlet airtemperature of 46-49° C.

OPADRY ® COMPLETE FILM 26.667 COATING SYSTEM 03F 180011 WHITE Metoprololsuccinate 15.2 Water 158.133 Total 200.0

The release of Metoprolol was tested according to the USP monograph forMetoprolol Succinate Extended-Release Tablets, Test 1 (The United StatesPharmacopeial Convention, Official Aug. 1, 2012). Results were:

Amount Time dissolved (h) (%) 1 23 4 29 8 47 20 102

Tesofensine release was tested at the one-hour time point and found tohave released fully.

The release profile of Metoprolol from Metoprolol 100 mg ER 25 mg IRtablets with separate Tesofensine—and Metoprolol IR films applied isshown in FIG. 3.

Example 7

Metoprolol ER tablet with film coating containing both Tesofensine andmetoprolol IR.

Metoprolol 100 mg ER tablets from example 1 (containing 95 mg Metoprololsuccinate) were film coated in a perforated drum coater with an aqueousfilm containing Tesofensine citrate plus Metoprolol succinate. Filmcomposition is given in the table. 312.5 mg of film solution was appliedfor each tablet corresponding to an increase in tablet weight of approx.16.5%. Spraying conditions were controlled to an outlet air temperatureof 45-50° C.

OPADRY ® COMPLETE FILM 30.00 COATING SYSTEM 03F 180011 WHITE Metoprololsuccinate 17.10 Tesofensine citrate 0.36 Water 177.54 Total 225.0

The release of Metoprolol was tested according to the USP monograph forMetoprolol Succinate Extended-Release Tablets, Test 1 (The United StatesPharmacopeial Convention, Official Aug. 1, 2012). Results were:

Amount Time dissolved (h) (%) 1 24 4 35 8 55 20 105

Tesofensine release was tested at the one-hour time point and found tohave released fully.

The release profile of Metoprolol from Metoprolol 100 mg ER and 25 mg IRtablets with combined Tesofensine/Metoprolol film applied is shown inFIG. 3.

Example 8

Carvedilol 80 mg ER tablets with separate coatings of Tesofensine andcarvedilol IR.

The tablets contain 0.5 mg IR Tesofensine, 80 mg ER Carvedilol and 20 mgIR Carvedilol, i.e. the ER:IR ratio is 80:20.

Carvedilol 400 mg/g pellets are prepared by mixing Carvedilol withmicrocrystalline cellulose and adding water in a high shear mixer untilproper moistening is achieved. The wet mass is extruded through a Bepexextruder and the form strings are rolled to squares on a spheronizer.The resulting pellets of about 1 mm in diameter are dried in a fluid-bedat 60° C. inlet air temperature. The carvedilol pellets are film coatedin a fluid-bed with bottom spray with a film to control the releasepattern. Approx. 5% weight increase is anticipated.

Carvedilol 252 g Microcrystalline cellulose 348 g Water 200 g Total800.0 Ethylcellulose 7 cps 6.75 g Methocel E 15 0.75 g Ethanol 96%69.375 g Water 23.125 Total 100.0

Carvedilol 80 mg ER tablets are produced by mixing Carvedilol 400 mg/gpellets with microcrystalline cellulose, lactose monohydrate,croscarmellose sodium and magnesium stearate. The mix is compressed totablets on a rotary tablet press, each tablet with a tablet weight of400 mg and size 7×14 mm each holding 80 mg Carvedilol. Tablets willrelease the drug in a zero order release rate.

Carvedilol 400 mg/g pellets 400.0 Microcrystalline cellulose 240.0Lactose monohydrate 135.8 Croscarmellose sodium 16.0 Magnesium stearate8.0 Total 800.0

Carvedilol 80 mg ER tablets are film coated in a perforated drum coaterwith an aqueous film containing Tesofensine citrate. Film composition isgiven in the table. 370.4 mg of film solution is applied for each tabletcorresponding to an increase in tablet weight of approx. 4.2%. Sprayingconditions were controlled to an outlet air temperature of 45-50° C.

Methocel E 15 8.0 Polyethylene glycol 6000 0.8 Tesofensine citrate 0.27Water 190.93 Total 200.0

The sub coated Carvedilol/Tesofensine tablets are further coated withthe final coating dispersion given in the next table. 313.6 mg of filmsolution is applied for each tablet corresponding to an increase intablet weight of approx. 14.8%. Spraying conditions are controlled to anoutlet air temperature of 46-49° C. The amount of Carvedilol in the IRfilm coating corresponds to 20 mg Carvedilol.

OPADRY ® COMPLETE FILM 26.667 COATING SYSTEM 03F 180011 WHITE Carvedilol12.7536 Water 160.579 Total 200.0

The expected dissolution profile for Carvedilol in a pharmaceuticalproduct comprising 80 mg extended release Carvedilol and 20 mg immediaterelease Carvedilol is depicted in FIG. 4. The dissolution profile ismeasured using a USP type 1 dissolution instrument using 500 ml pH 1.45for two hours and then increasing pH to 7 and volume to 900 ml. The testis performed at 37° C. with 50 rpm stirring for 20 hours.

Example 9

Carvedilol 40 mg ER tablets with separate coatings of Tesofensine andcarvedilol IR.

The tablets contain 0.5 mg IR Tesofensine, 40 mg ER Carvedilol and 10 mgIR Carvedilol, i.e. the ER:IR ratio is 80:20.

Carvedilol 40 mg ER tablets are produced by mixing Carvedilol 400 mg/gpellets (from example 8) with microcrystalline cellulose, lactosemonohydrate, croscarmellose sodium and magnesium stearate. The mix iscompressed to tablets on a rotary tablet press, each tablet with atablet weight of 400 mg and size 7×14 mm each holding 40 mg Carvedilol.Tablets will release the drug in a zero order release rate.

Carvedilol 400 mg/g pellets 200.0 Microcrystalline cellulose 320.0Lactose monohydrate 255.8 Croscarmellose sodium 16.0 Magnesium stearate8.0 Total 800.0

Carvedilol 40 mg ER tablets are film coated in a perforated drum coaterwith an aqueous film containing Tesofensine citrate. Film composition isgiven in the table. 370.4 mg of film solution is applied for each tabletcorresponding to an increase in tablet weight of approx. 4.2%. Sprayingconditions were controlled to an outlet air temperature of 45-50° C.

Methocel E 15 8.0 Polyethylene glycol 6000 0.8 Tesofensine citrate 0.27Water 190.93 Total 200.0

The sub coated Carvedilol 40 mg ER/Tesofensine tablets are furthercoated with the final coating dispersion given in the next table. 313.6mg of film solution is applied for each tablet corresponding to anincrease in tablet weight of approx. 12.4%. Spraying conditions arecontrolled to an outlet air temperature of 46-49° C. The amount ofCarvedilol in the IR film coating corresponds to 10 mg Carvedilol.

OPADRY ® COMPLETE FILM 26.667 COATING SYSTEM 03F 180011 WHITE Carvedilol6.3768 Water 166.956 Total 200.0

The expected dissolution profile for Carvedilol in a pharmaceuticalproduct comprising 40 mg extended release Carvedilol and 10 mg immediaterelease Carvedilol is depicted in FIG. 4. The dissolution profile ismeasured using a USP type 1 dissolution instrument using 500 ml pH 1.45for two hours and then increasing pH to 7 and volume to 900 ml. The testis performed at 37° C. with 50 rpm stirring for 20 hours.

What is claimed:
 1. A pharmaceutical composition comprising a. a firstcomposition comprising an extended release (ER) composition of a betablocker or a pharmaceutically acceptable salt thereof, b. a secondcomposition comprising an tesofensine or a pharmaceutically acceptablesalt thereof, and c. a third composition comprising an immediate release(IR) composition of a beta blocker of a pharmaceutically acceptable saltthereof.
 2. The pharmaceutical composition of claim 1, wherein the betablocker in the first composition and the third composition is metoprololor metoprolol tartrate.
 3. The pharmaceutical composition of claim 1,wherein the beta blocker in the first composition and the thirdcomposition is carvedilol or a pharmaceutically acceptable salt thereof.4. The pharmaceutical composition of claim 1, wherein the beta blockerin the first composition and the third composition is alprenolol,amosulalol, bucindolol, carteolol, levobunolol, mepindolol,metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol,sotalol, or timolol, or a pharmaceutically acceptable salt thereof. 5.The pharmaceutical composition of claim 1, wherein the beta blocker inthe first composition and the third composition is acebutolol, atenolol,betaxolol, bisoprolol, esmolol, landiolol, metoprolol, nebivolol, or apharmaceutically acceptable salt thereof.
 6. The pharmaceuticalcomposition of claim 1, wherein the beta blocker in the firstcomposition and the third composition is carvedilol, celiprolol,labetalol, or a pharmaceutically acceptable salt thereof.
 7. Thepharmaceutical composition of claim 1, wherein the beta blocker in thefirst composition and the third composition is butaxamine or apharmaceutically acceptable salt thereof.
 8. The pharmaceuticalcomposition of claim 1, wherein the tesofensine is tesofensine freebase, tesofensine citrate, or tesofensine tartrate.
 9. Thepharmaceutical composition of claim 1, wherein the the secondcomposition is a first coating applied to the first composition.
 10. Thepharmaceutical composition of claim 1, wherein the third composition isa second coating applied to a first coating comprising the secondcomposition.
 11. The pharmaceutical composition of claim 1, wherein thefirst composition constitutes a tablet core coated with a coatingcomprising the second composition and the third composition.
 12. Thepharmaceutical composition of claim 1, wherein the first compositioncomprises pellets comprising: a. an inert pellet core; b. a drug layercomprising the beta blocker or a pharmaceutically acceptable saltthereof, which layer covers the inert core; and c. a controlled releaselayer thereon.
 13. The pharmaceutical composition of claim 12, whereinthe inert pellet core comprises sugar spheres coated with a plasticizedfilm sub-coat of a hydrophobic film coating polymer plasticized with ahydrophilic and a hydrophobic plasticizer; the drug layer comprises thebeta blocker or a pharmaceutically acceptable salt thereof and a binder;the controlled release layer comprises a plasticized film coat of ahydrophobic film coating polymer plasticized with a hydrophilic and ahydrophobic plasticizer, and wherein the pellets are mixed with a finaltableting blend comprising a powder mixture of one or more fillers,disintegrants, glidants, or lubricants, or a combination thereof. 14.The pharmaceutical composition of claim 13, wherein the hydrophobic filmcoating polymer comprises ethyl cellulose, the hydrophilic plasticizercomprises polyethylene glycol, the hydrophobic plasticizer comprisesdibutyl sebacate, the beta blocker is metoprolol succinate, the bindercomprises povidone, and the powder mixture comprises starlac, syloid,crospovidone, and magnesium stearate.
 15. The pharmaceutical compositionof claim 1, wherein the first composition comprises a controlled releaselayer comprising an admixture of: an ethylacrylate/methylmethacrylatecopolymer, a surfactant, and sodium stearyl fumarate, wherein thecontrolled release layer has been deposited from a water-containingliquid and the amount of the ethylacrylate/methylmethacrylate copolymerin the film coat is in the rage of 80-99.5% (w/w).
 16. Thepharmaceutical composition of claim 1, wherein the composition is in theform of a pharmaceutical dosage form.
 17. The pharmaceutical compositionof claim 16, wherein the pharmaceutical dosage form is a tablet or acapsule.
 18. The pharmaceutical composition of claim 16, wherein thedosage form comprises an amount of 25-200 mg of the beta blocker or apharmaceutically acceptable salt thereof in the first composition. 19.The pharmaceutical composition of claim 16, wherein the dosage formcomprises an amount of 0.1-1 mg of the tesofensine of a pharmaceuticallyacceptable salt thereof in the second composition.
 20. Thepharmaceutical composition of claim 16, wherein the dosage formcomprises an amount of 5-100 mg of the beta blocker or apharmaceutically acceptable salt thereof in the third composition. 21.The pharmaceutical composition of claim 1, wherein the ratio of extendedrelease beta blocker to immediate release beta blocker is 75-95:25-5.22. The pharmaceutical composition of claim 1, comprising 25-200 mg ofthe extended release beta blocker or a pharmaceutically acceptable saltthereof, 5-50 mg of the immediate release beta blocker or apharmaceutically acceptable salt thereof, and 0.1-1.5 mg tesofensine.23. A method of treating obesity, an obesity-associated disorder,diabetes, metabolic syndrome, dyslipidemia, atherosclerosis,drug-induced obesity, an overeating disorder, bulimia nervosa, bingeeating disorder, compulsive over-eating, impaired appetite regulation,nonalcoPholic fatty liver disease, or nonalcoholic steatohepatitis in asubject comprising administering to the subject a pharmaceuticalcomposition of claim
 1. 24. The method of claim 23, wherein the diabetesis type 2 diabetes.
 25. The method of claim 23, wherein the diabetes ispre-diabetes.
 26. The method of claim 23, wherein the pharmaceuticalcomposition is administered once daily.